A retrospective cohort study on clinical characteristics of heart failure patients with HFrEF, HFmrEFand HFpEF in geriatrics of Northeastern China

Background: Heart failure (HF) has been considered as one of the leading cardiovascular disease with high morbidity and high mortality in the world. However, there is a lack of analysis on the clinical characteristics of different types of elderly HF patients in geriatrics of Northeastern China.We conducted this single-center, retrospective study to evaluate the clinical characteristics of HF patients with mid-range(HFmrEF), preserved (HFpEF) and reduced ejection fraction (HFrEF) in a Chinese cohort. Methods: The study was conducted on 1230 patients of age 60 or above, with HF from Jan. 02, 2014 to May 03, 2018 hospitalized in geriatrics department, the First Aliated Hospital of China Medical University. All the patients met the denition for HFrEF, HFmrEF and HFpEF according to 2016 European Society of Cardiology (ESC) guidelines.Targeted variables including demographics, vital signs, comorbidities and lab assessment results were compared among the three groups by Pearson’s χ2 test, and multivariate logistic regression analyses were performed for risk factor exploration on the three types of HF. Results:Of the 1230 patients included (78.28±9.0years, 67.15%male), there are 93 patients with HFrEF(7.5%), 56 patients with HFmrEF (4.5%) and 1081 patients with HFpEF (87.8%). Compared to patients with HFpEF, those with HFmrEF were more likely to have comorbid acute myocardial infarction, infection and coronary artery disease, had higher level of N-terminal pro B-type natriuretic peptide (NT-proBNP), cardiac troponin, blood urea nitrogen (BUN), white blood cell (WBC). And patients with HFpEF were more frequently to be female, to be older, and to have comorbid peripheral artery disease, but less frequently had AMI, CAD and kidney disease than those with HFrEF. However, patients with HFmrEF had no signicant difference from those with HFrEF. Multivariable analysis showed that comorbid atrial brillation,AMI and infection were associated with HFmrEF (p<0.05), whereas female, old age, comorbid hypertension,and PAD were associatedwithHFpEF, and CAD,kidney disease were associated with HFrEF (p<0.05). Conclusions:The results of our study supported that patients with HFmrEF were closer to patients with HFrEF in respect to most of the demographics andclinical characteristics observed, while showing certain differences from patients with HFpEF. local


Introduction
Heart failure (HF) is a complex clinical syndrome caused by any structural or functional impairment of ventricular lling orejection of blood [1].It has been considered as one of the major public health concerns with high mortality and economic burden of the patients all over the world. The number of patients hospitalized for HF increases by almost 10,000 per year due to the growing elderly population, and the economic burden has concomitantly increased a lot, correspondingly both in developed and developing countries.On the basis of 2016 European Society of Cardiology (ESC) guidelines and left ventricular ejection fraction (LVEF), HF could be classi ed into 3 types:HFpEF (with preserved EF, LVEF ≥50%), HFrEF (with reduced EF, LVEF<40%) and HFmrEF (with mid-range EF, LVEF of 40-49%) [3].Those three categories of HF have different underlying etiologies, demographics, comorbidities and responses to therapies [4].
Approximately 1-2% of the adultswere diagnosed as HF patientsin developed countries [5]. Especially, a recent study indicated the overall prevalence of HF was 2.2% in the US, varied from 0.7% of people aged 45-54 to 8.4% of those aged 75 and above [6]. With the aging of population, China will become the country with the most severe aging of population in the world.However,the incidence and epidemiological characteristics of different types of HF are rarely analyzed among the growing elderly population in China. Therefore, we conducted this single-center, retrospective study on patients with these three types of HF in geriatrics departmentof a cohort in Northeastern China.
Our study aims to evaluate the baseline characteristics, comorbidities and laboratory ndings, and explore the distribution of HF, and the key risk factors related to those three types of HF in the elderly patients of Northeastern China.

Study design and population
Baseline clinical characteristics including age, sex, status of smoking and alcohol use, vital signs including body mass index (BMI), blood pressure and pulse, comorbidities and laboratory ndings were compared and analyzed among the three groups of HF patients. BMI was calculated based on the formula BMI= mass/height. Dyslipidemia was determined by an elevation of the total cholesterol, the lowdensity lipoprotein (LDL) cholesterol and the triglyceride concentrations, and a decrease in the highdensity lipoprotein (HDL) cholesterol in the blood. Coronary artery disease (CAD)consisted of unstable angina pectoris (UAP), comorbid kidney disease (CKD), acute myocardial infarction (AMI) and the other heart diseases.Infection here included all infections throughout the body.
The study was approved by the local ethics committee from the First A liated Hospital of China Medical University(#2020232). All methods were performed in accordance with the relevant guidelines and regulations.

Statistical analysis
Statistical analysis was performed using SAS Statistical Software, Version 9.4 (SAS Institute, Inc., Cary, North Carolina). Continuous variables were presented as mean (SD) and independent t-test was used in comparisons with signi cance level of 0.05.Categorical variables were calculated as Count (%) and compared using χ 2 test with signi cance level of 0.05.Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95% confidence interval, and to find associated factors for the three HF groups. The p< 0.05 was considered statistically signi cant.
The overall population was 78.28±9.00years of age. The difference of age in patients withHFrEF (75.41±9.23) and those with HFpEF (78.60±8.91) werestatistically signi cant (p<0.05). With respect to gender, the different proportion of male/female in HFrEF and HFpEF was statistically signi cant with p <0.01. No signi cant difference in smoking and alcohol use was found between any two of these three HF groups.
In terms of vital signs, pulse was signi cantly lower in patients with HFpEF than patients with HFrEF(p<0.01) while systolic blood pressure (SBP) was signi cantly higher in patients with HFpEF than patients with HFrEF (p<0.01). SBP in patients with HFmrEF was signi cantly higher than patients with HFrEF (p<0.05). The only difference for body mass index (BMI) in these 3 HF groups was found between HFpEF and HFmrEF groups, whereas diastolic blood pressure (DBP) and body temperature were not signi cantly different among all the HF groups.

Comorbidity
Comorbid diseases and interventions included but not limited to malignancy, hypertension, chronic obstructive pulmonary disease (COPD), diabetes mellitus, dyslipidemia, atrial brillation, anemia, percutaneous coronary intervention (PCI), pacemaker and cerebrovascular accident/transient ischemic attack(CVA/TIA), unstable angina pectoris (UAP), high uric acid and gout (HUGA). The frequency of all the comorbidities above had no signi cant difference between patients with HFmrEF and HFrEF.

Laboratory Assessments
Laboratory assessments were performed for all enrolled HF patients and the pair-wise comparisons among the 3 groups was listed in Table 3. The levels of NT-proBNP, and BNP were the value of log transformation before analysis. The following laboratory parameters:NT-proBNP,BNP,cardiac troponin,WBC, neutrophil%, BUN, serum sodium, uric acid,weresigni cantly higher in patients with HFmrEF than those with HFpEF.In addition, NT-proBNP, LDH, BNP,WBC, neutrophil%,BUN, serum creatinine, serum sodium, D-dimer were also signi cantly higher in patients with HFrEF than those with HFpEF.But the levels ofcreatinekinase-MB and cardiac troponin were signi cantly higher in patients with HFpEF than with HFrEF.As for uric acid, there was no signi cant difference between these two groups. Meanwhile, the levels of BNP, LDH, and serum creatinine were signi cantly higher in patients with HFrEF than those of HFmrEF.
The other lab parameters observed but not mentioned above, including C-reactive protein, fasting blood glucose (FBP),serum potassium, hemoglobin etc., were comparable between any two of the three HF groups without any signi cant difference.   Table 4.There were 92 overall deaths (7.47%) in the HF patients during the study period, with a slightly higher unadjusted mortality rate seen in HFmrEF group (10.71%) than in HFpEF group (7.31%) or in HFrEF group (7.53%). However, there was no signi cant difference for the mortality rate among these three HF groups.

Risk factors associated with HFmrEF,HFrEF and HFpEF
The univariate analysis of the associated factors with HFmrEF, HFpEF and HFrEF was shown asforest plots inFigure 2 and multivariable logistic regression analysis was performed to obtainthe odds ratios (Table 5). The resultsof univariate and multivariable logistic regression indicatedthatcomorbidatrial brillation, AMI and infectionwere associated with HFmrEF, whereas female gender, old age, comorbid hypertension and PADwere associated with HFpEF, and CAD, kidney disease were associated with HFrEF (see Table 6).
Among all baseline characteristics and clinical parameters, AMI had the highest odds ratio for HFmrEF (4.21), while female and CAD had the highest odds ratio for HFpEF (2.55) and HFrEF (3.02), respectively.
Our univariate analysis also indicated that baseline characteristics, comorbid features and laboratory results were comparable between HFmrEF patients and HFrEF patients, which were displayed in Supplemental Figure 1 after the reference section.

Discussion
Our study was a single-center, retrospective study conducted in Shenyang, a provincial capital city in northeastern China,to provide data on the demographics and clinical characteristics of geriatrics inpatients with HFrEF, HFmrEF and HFpEF.HFmrEF, as a newly de ned HF type by ESC in2016, was investigated and compared with other HF types, revealing that patients with HFmrEF was closer to patients with HFrEF than patients with HFpEF in terms of most of the clinical baseline characteristics.
In our study, HFpEF accounted for 87.8% of all HF patients included, while HFmrEF and HFrEF accounted for 4.5% and 7.5% respectively. The prevalence of HFmrEF 4.5% in our study was muchlower thanin other studies(16%,24% or 17%) [7][8][9].Previous studies were mostly based on the statistical results of patients with HF, or registered in hypertension, HF centers and other related data [10][11][12]. In contrast, this study was on inpatients of geriatrics department, so it is much more asymptotic to the incidence of HF in the elderly population, and will be more conducive to reminding geriatricians of identifying HF patients, and following up analysis on HFpEF patients with a large proportion, and exploring more factors affecting heart function to further guide the clinical treatment of HFpEF [5].The mean age of HF patients included was 78.28, higher than those reported in other studies [5],which could be explained by the fact that our patients were enrolled from the geriatric department of a hospital where usually older patients are admitted.Previous studies including older patients showed a higher frequency of HFpEF [13]. And our nding was in accordance with that. ThatHFpEFpatients were older than HFmrEF and HFrEF patients (78.6 vs 77.05 and 75.41).In addition,our patients were certainly from geriatrics department, not just cardiovascular department.This may be the reason for the largest proportion of HFpEF.Asub-cohort of the PROTECT trial the proportion of patients with HFpEF is 13%.The included patients have a history of HF, who were admitted with acute HF and mild to moderate renal dysfunction,age≥18 years. [14].In aretrospective study from Japan,HFrEF HFmrEF and HFpEF accounted for 36%,21% and 43% respectively.Patients included in this study were all admittedfor acute decompensated HF [15].
In Turkey-the APOLLON study, patients with HFpEF were more likely to be women, withlower frequency of coronary artery disease and myocardial infarction and kidney disease than patients with HFrEF [16].
Similarly, in our study, women accounted for a higher frequency of HFpEF, which is consistent with this, considering that this phenomenon may be related to the greater exposure of male patients to cardiovascular disease risk factors [17].
The acute myocardial infarction and kidney disease including both chronic kidney disease and acute kidney injury were analyzed in our study. Our study showed that atrial brillation was most frequently observed in patients with HFmrEF (28.57%), while it was mostly observed in patients with HFpEF (38.2%) in the APOLLON study [16]. The frequency of atrial brillation in the present study appeared lower than another study from Swedish Heart Failure Registry(21.51%vs 53%, 28.57% vs60% and 18.22vs65%) in HFrEF, HFmrEF and HFpEF patients respectively [18], but slightly higher than the CHARM study (Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity) with the prevalence of AF 19% in HFpEF and 17% in HFrEF [19].One reason for the different prevalence of AF among these studies might be the different cohort selection.Our patients are all from the geriatrics department, who are older and have a higher incidence of atrial brillation.
When comparing the three HF patient groups for comorbidities, we either found that they were differently distributed between patients with HFmrEF and HFpEF (AMI, infection, CAD), or between HFpEF and HFrEF (kidney disease, AMI, PAD and CAD), but failed to nd any signi cant difference betweenpatients with HFmrEF and HFrEF for all these comorbidities. Moreover, our multivariable analysis showed that CAD was associated with HFrEF, while AMI, as a part of CAD, was associated with HFmrEF. A few previous studies also showed that the frequency of CAD in HFmrEF patients was similar toHFrEF patients, both higher than HFpEF patients [20][21][22].
Similar to the APPLON study, some comorbidities including malignancy, COPD (chronic obstructive pulmonary disease), diabetes mellitus, anemia and CVA_TIA (cere brovascular accident/transient ischemic attack) were comparable between HFmrEF patients and HFpEF patients [16].Previous studies have shown hypertension was more frequently observed in HFpEF patients. But in our study, hypertension showed a similar tendency with a higher percentage found in HFpEF patients than HFrEF and HFmrEF patients, even not statistically signi cantly. In our multivariable analysis, indeed hypertension was found to be associated with HFpEF besides female, old age and PAD (peripheral artery disease).
The level of NT-proBNP, BNP,blood urea nitrogen, creatinine was signi cantly lower in patients with HFpEF than those with HFmrEF or HFrEF, which was in accordance with the previous studies [16,23]. This may be explained with the prevalence of kidney disease tending to be higher in HFmrEF or HFrEF patients than in HFpEF patients.
However, some studies have presented different results. Josephine et al. performed a meta-analysis on the characteristics and prognosis of HFrEF, HFmrEF and HFpEF patients and concluded that HFmrEF was a distinctive category in between HFrEF and HFpEF [24].In a prospective study based on the Sweden HF Registry cohort, HFmrEF resembled HFrEF for some characteristics, but resembled HFpEF for some other characteristics and HFmrEF was concluded to be an intermediate phenotype between HFrEF and HFpEF [21].In our study, HFmrEF showed no signi cant difference with HFrEF in terms of all the comorbidities observed and most of the lab parameters measured including NT-proBNP, creatine kinase-MB, cardiac troponin, uric acid, WBC etc. Our study revealed that a similar overall disease pro le might be shared in between patients with HFmrEF and HFrEF. HFmrEF was a disease entity more similar toHFrEF than to HFpEF, which seemed to be contradictory to these previous studies [24,21]. But considering the difference in the proportion of HFrEF, HFmrEF and HFpEF (56%, 21% and 23% in the Sweden HF study and 7.5%, 4.5% and 87.8% in our study) and the difference in the overall HF population selection (from a HF registry covering all Sweden and from geriatric department of a hospital in China) in the two studies, and other underlying differences in the operation and process of the related data, it is not surprising that the results may differ somehow. At the very least, our study provided a new evidence about the distribution of related variables among different HF types in this particular HF population, and may potentially contribute to the treatment decision toward HF in the future.
Our nding suggested that the mortality rate was comparable among all three HF groups, in consistent with previous studies where comparable mortality was observed in HFpEF and HFrEFgroups [25]. But the overall mortality in current study was lower (7.22%) for patients with HFpEF than in other studies showing a one-year mortality of 19 to 29% [26]. One explanation for this was that our mortality rate was based on the in-hospital deaths only, while theirs was based on both in and out of the hospital with follow-up data collected [26]. Notably our study lacked etiology mortality analysis, so what caused these deaths among these HF patients remained unclear. With the complexity and heterogeneity of HF, apparently more comprehensive studies are needed to better determine the long-term prognosis of patients according to etiology.

Limitation
The results of the present study should be interpreted in the context of certain limitations.First, it was a retrospective study, lacking of follow-upinformation and the patient's out-of-hospital death record, so all the data were analyzed on the basis of hospitalization period only. We assessed associations between clinical characteristics and LVEFgroups, but we could not demonstrate causality and survival model for the prognosis study.Our multivariable analysis showed thatatrial brillation, AMI and infectionwere the risk factors associated with HFmrEF, while female, old age, hypertension and PAD were associated with HFpEF, and CAD and kidney disease were associated with HFrEF, but we could not conclude whether these conditions or factors preceded HF or were consequences of HF.
Secondly, the number of patients with HFmrEF and HFrEF was relatively small so thatthe interpretation of our results might be limited. Therefore, future trials will require increasing enrollment of patients with HFrEF and HFmrEFto better understand the characteristics and clinical outcomes and eventually help evaluate possible therapeutic options for HF patients.
Thirdly, we did not perform etiology analysis for HF. If this could be included in the future studies, it might be helpful for the pathophysiology study of HFpEF and HFmrEF, thus contributing to the medication selection.
Finally, the study participants were from a single hospital in China, despite of its very rst rank in general hospitals in northeastern China, it is still uncertain whether these findings can be generalized to patients in other areas of China.

Conclusions
This was a retrospective study conducted on HF patients in a hospital located in northeastern China.
Heart failure with preserved ejection fraction(HFpEF, LVEF>50%)represented the majority of all cases of HF in the present study. Heart failure with mid-range ejection fraction (HFmrEF, LVEF40-49%), as a newly de ned type of HF, was closer to heart failure with reduced ejection fraction (HFrEF, LVEF<40%) in terms of most of the demographics, comorbidities and laboratory parameters observed, with certain differences found between HFmrEF and HFpEF groups, more so between HFrEF and HFpEF for these observed features. Overall, more comprehensive studies including higher proportion of patients with HFmrEF, follow-up study are needed to better understand this newly de ned HF category, to further identify the determinants accounting for its signi cant potential differences from the other two HF groups, survival analysis and ultimately to guide beneficial therapies.

Declarations
Ethics approval and consent to participate The study was approved by the ethics committee of the First A liated Hospital of China Medical University(#2020232). All methods were performed in accordance with the relevant guidelines and regulations.The need for informed consent was waived because of the retrospective nature of the analysis.

Consent for publication
Not applicable.

Availability of data and materials
The datasets generated and analysed during the current study are not publicly available due fact that our project need to be continued, but are available from the corresponding author on reasonable request.